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Summary: Although intramuscular (i.m.) administration is the most commonly used route for licensed vaccines, subcutaneous (s.c.) delivery is being explored for several new vaccines under development. Here, we use rhesus macaques, physiologically relevant to humans, to identify the anatomical compartments and early immune processes engaged in the response to immunization via the two routes. Administration of fluorescently labeled HIV-1 envelope glycoprotein trimers displayed on liposomes enables visualization of targeted cells and tissues. Both s.c. and i.m. routes induce efficient immune cell infiltration, activation, and antigen uptake, functions that are tightly restricted to the skin and muscle, respectively. Antigen is also transported to different lymph nodes depending on route. However, these early differences do not translate into significant differences in the magnitude or quality of antigen-specific cellular and humoral responses over time. Thus, although some distinct immunological differences are noted, the choice of route may instead be motivated by clinical practicality. : Route of immunization, especially intramuscular versus subcutaneous administration, is often debated. Ols et al. use a rhesus macaque model to determine the tissues targeted by a nanoparticle vaccine administered by either route. The authors demonstrate that tissue dissemination is route dependent, but innate and adaptive immune responses develop comparably. Keywords: vaccination, intramuscular, subcutaneous, antigen transport, HIV envelope glycoprotein, dendritic cell, follicular dendritic cell, monocytes, lymph node, B cell follicle

Summary: Using non-human primates (NHPs), mice, and human primary cells, we found a role for interleukin-10 (IL-10) in the upregulation of the tissue-resident memory T cell (TRM) marker CD103. In NHPs, intravenous, but not subcutaneous, immunization with peptide antigen and an adjuvant combining an agonistic anti-CD40 antibody plus poly(IC:LC) induced high levels of CD103+ TRMs in the lung, which correlated with early plasma IL-10 levels. Blocking IL-10 reduced CD103 expression on human T cells stimulated in vitro with the adjuvant combination as well as diminished CD103 on lung-resident T cells in vivo in mice. Monocyte-produced IL-10 induced the release of surface-bound transforming growth factor β (TGF-β), which in turn upregulated CD103 on T cells. Early TGF-β imprinted increased sensitivity to TGF-β restimulation, indicating an early commitment of the T cell lineage toward TRMs during the priming stage of activation. IL-10-mediated TGF-β signaling may therefore have a critical role in the generation of TRM following vaccination. : Thompson et al. outline a role for early IL-10 following immunization in the release of TGF-β and subsequent differentiation of CD103+ TRMs. Using a combination of non-human primate, human, and murine systems, the authors demonstrate that blocking IL-10 reduces CD103 expression, whereas delivery of IL-10 can augment a CD103+ phenotype. Keywords: tissue-resident memory T cells, vaccine, anti-CD40, toll-like receptor, IL-10, TGF-beta, monocyte, T cell, non-human primate, TRM